There is a fundamental gap between the practical use of blue-green algae (BGA) as complementary and alternative medicine (CAM) substances and our understanding of their safety and biological functions. The long-term research goal is to identify and develop natural sources for CAM for promoting optimal health. The objectives of this project are to assess safety and athero-protective property of a newly cultivated BGA species Nostoc commune var. sphaeroides Kutzing (NO) and to elucidate the molecular mechanisms underlying the athero-protection. Spirulina plantensis (SP) will be used as a control BGA for comparison because it is the most common cultured BGA species that is known to be free of algal toxins. Our central hypothesis is that NO is a safe CAM substance that have hypocholesterolemic (cholesterol-lowering) and hypotriglyceridemic (triglyceride-lowering) properties, ultimately retarding the progress of atherosclerosis development. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Evaluate safety of BGA in vivo and in vitro;2) Assess lipid-lowering effects of BGA and identify molecular mechanisms;and 3) Determine anti-atherogenic roles of BGA in mice. The proposed work is innovative in that no study exists to assess safety of BGA supplementation in vivo and to mechanistically evaluate their efficacy in athero-protection using an animal model of atherosclerosis. Additionally, it is the first study that examines biological functions of newly cultivated NO in comparison with cultivated SP that is currently consumed as a dietary supplement. Cultivation of BGA can circumvent controversial health issues on BGA as quality and toxin contamination can be tightly controlled during production. In this regard, cultivated NO and SP present their worth for investigation on biological functions over naturally-harvested BGA species. With respect to expected outcomes, collective works proposed in specific aims 1-3 are expected to provide insights into BGA toxicity and athero-protective property with the elucidation of molecular mechanisms. Such results will have an important positive impact on public's health by providing scientific foundation for human clinical trials to test efficacy of BGA as effective and reliable CAM substances to reduce the risk of CVD. Therefore, the proposed research fits well to the mission of NCCAM "to explore complementary and alternative healing practices in the context of rigorous science, training CAM researchers, and disseminating authoritative information to the public and professional communities." PUBLIC HEALTH RELEVANCE: Blue-green algae products have been introduced as a dietary supplement to meet increasing public's interest in using natural products for preventive and therapeutic means for heart disease prevention. Safety and biological functions of various BGA species, however, are not properly studied. This project will assess safety and athero-protective property of newly cultivated blue-green alga Nostoc commune var. sphaeroides Kutzing together with Spirulina plantensis, which is the most common cultivated BGA in the current dietary supplement market. The project addresses an important yet under-investigated area of basic research on complementary and alternative medicine (CAM) substances that will have a positive impact on public's health by providing scientific foundation for human clinical trials to test efficacy of BGA as effective and reliable CAM substances to reduce the risk of cardiovascular disease.